Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
  • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
  • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
  • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
  • C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4

Definitions

• This invention relates to novel quinolinecarboxylic acid compounds and an antimicrobial agent containing said compound as an active ingredient. More particularly, it relates to 6-fluoro-1,4-dihydro-7-(4-hydroxypiperazin-1-yl)-4-oxoquinoline-3-carboxylic acid compounds of the formula: wherein R is ethyl, 2-fluoroethyl or cyclopropyl, and X is hydrogen atom or fluorine atom, and a pharmaceutically acceptable salt thereof, and an antimicrobial agent containing said compound as an active ingredient.
• the present inventors have studies to find novel quinolinecarboxylic acid compounds having improved anti microbial activities in vivo by replacing the piperazinyl group at 7-position by various substituted piperazinyl groups, and have found that introduction of 4-hydroxy-piperazinyl group is effective for improvement of the antimicrobial activities in vivo.
• An object of the invention is to provide novel quinolinecarboxylic acid compounds having improved antimicrobial activities in vivo.
• Another object of the invention is to provide novel 4-hydropiperazinyl- quinolinecarboxylic acid compounds and a pharmaceutically acceptable salt thereof.
• a further object of the invention is to provide an antimicrobial agent containing as an active ingredient the novel 4-hydrox- ypiperazinylquinolinecarboxylic acid compound or a pharmaceutically acceptable salt thereof.
• the compounds of this invention have the formula (I) as set forth hereinbefore, and the novel quinolinecarboxylic acid compounds (I) and a pharmaceutically acceptable salt thereof have superior antimicrobial activities in vivo to the known 7-piperazinylquinolinecarboxylic acid compounds and have less toxicity.
• Preferred specific compounds of this invention are 1-ethyl-6-fluoro-1,4-dihydro-7-(4-hydroxypiperazin-1-yl)-4-oxoquinoline-3-carboxylic acid, 1-cyclopropyl-6-fluoro-1,4-dihydro-7-(4-hydroxypiperazin-1-yl)-4- oxoquinoline-3-carboxylic acid, 1-ethyl-6,8-difluoro-1,4-dihydro-7-(4-hydroxypiperazin-1-yl)-4-oxoquinoline-3-carboxylic acid, 6,8-difluoro-1-(2-fluoroethyly-1,4-dihydro-7-(4-hydroxypiperazin-1-yl)-4-oxoquinoline-3-carboxylic acid, and 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(4-hydroxypiperazin-1-yl)-4-oxo
• the compounds of this invention include a pharmaceutically acceptable salt of the compounds of the formula (I).
• Preferred pharmaceutically acceptable salts are acid addition salts, such as hydrochloride, methanesulfonate, etc.
• the compounds of this invention can be prepared by various processes, for instance, by Process A and Process B as mentioned below.
• Process A and Process B as mentioned below.
• the compounds of the formula (I) wherein R is ethyl or cyclopropyl and X is hydrogen atom or fluorine atom can also be prepared by Process C as mentioned hereinafter. wherein R and X are as defined above, and Y is fluorine atom or chlorine atom.
• the compounds (I) can be prepared by reacting a known compound (II) with an acid addition salt (e.g. dihydrochloride) of 1-hydroxypiperazine (III) in a solvent in the presence of a base.
• the compound (III) is usually used in an amount of 1 to 4 moles, preferably 12 to 3 moles, per 1 mole of the compound (II).
• the base is preferably tertiary amines (e.g. triethylamine), which is usually used in an amount of 4 to 15 moles per 1 mole of the compound (II).
• Suitable solvent is polar solvents, such as dimethylsulfoxide, dimethyl formamide, pyridine tetrahydrofuran, acetonitrile, methanol and ethanol.
• the reaction is usually carried out at a temperature of 50 to 200°C, preferably 60 to 150°C, for 30 minutes to 5 hours.
• the starting compound (III) used in the above Process A i.e. acid addition salt (e.g. dihydrochloride) of 1-hydroxypiperazine can be prepared, for example, by a process as shown in the following reaction - scheme:
• 1-formylpiperazine (IV) is reacted with ethyl acrylate to give a compound (V), and the resulting compound is treated with an oxidizing agent (e.g. hydrogen peroxide) preferably in the presence of a catalyst (e.g. sodium tungstate) to give 4-hydroxy-1-formylpiperazine (VI).
• an oxidizing agent e.g. hydrogen peroxide
• a catalyst e.g. sodium tungstate
• the compound (VI) is hydrolyzed with hydrochloric acid to give 1-hydroxypiperazine dihydrochloride (III). wherein R and X are as defined above.
• the compounds (I) can be prepared by reacting a compound (VII) with an oxidizing agent in an organic solvent (e.g. chloroform, methanol, etc.).
• the oxidizing agent includes m-chloroperbenzoic acid, peracetic acid, hydrogen peroxide, and the like, which is usually used in an amount of 1.0 to 5.0 moles, preferably, 1.2 to 3.0 moles, per 1 mole of the compound (VII).
• the reaction is usually carried out at a temperature of 0°C to 100°C for 3 to 24 hours.
• R is ethyl or cyclopropyl
• X is hydrogen atom or fluorine atom.
• a 3-cyanoquinoline compound (VIII) is reacted with a 1-hydroxypiperazine acid addition salt (e.g. dihydrochloride) (III) in a solvent in the presence of a base to give a 7-(4-hydroxypiperazin-1-yl)-3-cyanoquinoline compound (IX).
• the compound (III) is usually used in an amount of 1 to 4 moles, preferably 1.2 to 3 moles, per 1 mole of the compound (VIII).
• the base is preferably tertiary amines (e.g. triethylamine), which is usually used in an amount of 4 to 15 moles per 1 mole of the compound (VIII).
• Preferred solvent is a porlar solvent, such as dimethylsulfoxide, dimethylformamide, etc.
• the reaction is usually carried out at a temperature of 50 to 150°C, preferably 80 to 130°C, for 1 to 8 hours.
• the compound (IX) is subsequently hydrolyzed with an acid, and the resulting acid addition salt is neutralized to give the compound of the formula (I) wherein R is ethyl or cyclopropyl and X is hydrogen atom or fluorine atom.
• Preferred acid used for the hydrolysis is, for example, hydrochloric acid.
• the reaction is usually carried out at a temperature of 70 to 100°C for 6 to 10 hours.
• the 3-cyanoquinoline compounds (VIII) used in the above Process C can be prepared, for example, by a process as shown in the following reaction'scheme: wherein R is ethyl or cyclopropyl and X is hydrogen atom or fluorine atom.
• a benzoic acid compound (X) is reacted with thionyl chloride in the presence of a catalytic amount of dimethylformamide to give an acid chloride (XI).
• the compound (XI) is subsequently reacted with methyl cyanoacetate in the presvne of sodium hydride and then acidified with hydrochloric acid to give a compound (XII).
• the compound (XII) is treated with aqueous sodium hydroxide and then acidified with hydrochloric acid to give a compound (XIII).
• the resulting compound (XIII) is reacted with ethyl orthoformate in the presence of acetic anhydride to give a compound (XIV).
• the compound (XIV) is reacted with ethylamine or cyclopropylamine to give a compound (XV).
• the compound (XV) is finally treated with sodium hydride to give a 3-cyanoquinoline compound (VIII).
• the compounds (I) of the invention as prepared by the above processes can be isolated and purified from the reaction mixture by a conventional purification method, for example, by silica gel column chromatography or recrystallization.
• the compounds (I) can be converted into a salt thereof by treating them with an acid or a base in a usual manner.
• the compounds (I) and a pharmaceutically acceptable salt thereof are used as an antimicrobial agent by administering to animals, particularly human patients, by oral route.
• These compounds are usually used in conventional pharmaceutical preparations, such as tablets, granules, fine granules, powders, syrups, and the like, which are prepared by admixing with conventional pharmaceutically acceptable nontoxic carriers or diluents, such as corn starch, lactose, magnesium stearate, fine crystalline cellulose, kaolin, calcium carbonate, talc, etc., or capsules which are prepared by packing the above-mentioned granules, fine granules or powders into capsules.
• the dose of the compounds of this invention may vary in accordance with age and body weight of the patients and severity of diseases, and the like, but is usually in the range of 0.5 to 30 mg/kg of body weight/day, preferably 2 to 20 mg/kg of body weight/day [as the compound (I)], which may be administered once a day or may be divided into 2 to 4 times per day.
• the compounds of this invention show the same as or somewhat inferior antimicrobial activities in vitro in comparison with the known 7-piperazinylquinolinecarboxylic acid compounds, but show superior antimicrobial activities in vivo to the latter. That is, according to comparative experiments, the compounds of this invention showed the same or somewhat larger MIC (minimum inhibitory concentration) in comparison with the corresponding reference compounds, but showed superior activities in the infectious protection test in mice to the latter (cf. Experiment 1, Tables 1 to 5).
• the compounds of this invention show lower toxicity (cf. Experiment 2).
• mice was daily observed for one week, and from the survival number of mice after one week, the 50 % effective dose (ED 50 ) was calculated by Weil method.
• Each test compound was suspended in 0.5 % (W/V) aqueous sodium carboxymethyl cellulose solution, and the suspension was orally administered to ddY male mice (5 weeks age, weighing 20 -25 g, one group: 10 mice) (in case of Reference Compound B, it was orally administered in the form of a solution in sterilized distilled water). The number of dead mice during 2 weeks after administration was counted, and the acute toxicity (LD so ) was calculated by Weil method.
• the compounds of this invention are effective as an antimicrobial agent with high safety.
• 1-Hydroxypiperazine dihydrochloride is prepared according to the following procedures from (1) to (3).
• the crude 4-ethoxycarbonylethyl-1-formylpiperazine (114 g) prepared as described above is dissolved in water (500 ml) and sodium tungstate dihydrate (7.25 g) is added to the solution.
• sodium tungstate dihydrate (7.25 g) is added to the solution.
• 31 % hydrogen peroxide (82 ml) is added dropwise to the solution and the mixture is stirred for one hour.
• the reaction mixture is stirred for 3 hours at room temperature and for another 5 hours at a temperature of 50 -55°C.
• the resulting reaction mixture is then shaken with ethyl acetate (300 ml).
• the aqueous layer is evaporated under reduced pressure to remove water to yield a dark brown oil.
• Dimethylformamide (0.6 ml) is added to a mixture of 2,3,4,5-tetrafluorobenzoic acid (100 g) and thionyl chloride (135 ml), and the mixture is heated under reflux with stirring for 7 hours.
• the reaction mixture is condensed under vacuum to yield crude 2,3,4,5-tetrafluorobenzoyl chloride as a pale yellow oily residue - (110.5 g).
• Methyl cyanoacetate (51.1 g) is added dropwise to a suspension of sodium hydride (43.3 g, in oil, 55 - 65 w/w %) in dry tetrahydrofuran (600 ml) while maintaining the internal temperature between 15°C and 20°C on an ice bath.
• sodium hydride (43.3 g, in oil, 55 - 65 w/w %)
• dry tetrahydrofuran 600 ml
• To the reaction mixture is added dropwise the crude 2,3,4,5-tetrafluorobenzoyl chloride (110.5 g) as obtained above, and the mixture is stirred while maintaining the internal temprature as above.
• methylene chloride is added to the reaction mixture and the reaction product is extracted with 3 % aqueous bicarbonate. The extract is then washed with methylene chloride to remove the remaining cyanoacetate.
• Methyl 2-cyano-3-hydroxy-3-(2,3,4,5-tetrafluoro-phenyl)acrylate (75.1 g) is added to a solution of sodium hydroxyde (110 g) in water (1.1 liter) and the mixture is stirred at room temperature for 26 hours. To the reaction mixture is added ice (1.3 Kg) and conc. HCI. After 1 hour, the precipitate is filtered and washed with dil. HCI to yield 2-(2,3,4,5-tetrafluorobenzoyl)acetonitrile (52.7 g) as a light cream colored powder, m.p. 60 -61 °C.
• a solution of cyclopropylamine (3.3 g) in chloroform (20 ml) is added dropwise to a solution of 3- ethoxy-2-(2,3,4,5-tetrafluorobenzoyl)acrylonitrile (14.0 g) in chloroform (50 ml) with maintaining the internal temperature between 6°C and 8°C by uning an ice bath.
• the mixture is allowed to stand overnight at room temperature and then concentrated under vacuum to yield an orange oily residue.
• the oily residue is dissolved in ethanol and the ethanol is removed in vacuum to afford a crystalline residue.
• reaction mixture is poured into hexane (300 ml), and the resulting precipitate is filtered and washed with hexane and water to yield 1-cyclopropyl-3-cyano-1,4-dihydro-4-oxo-6,7,8-trifluoroquinoline (10.2 g) as a colorless powder, m.p. 217 - 218°C.
• the insoluble substance is filtered and then recrystallized from a mixture of dimethylformamide and water to afford 1-cyclopropyl-6-fluoro-1,4-dihydro-7-(4-hydroxypiperazin-1-yl)-4-oxoquinoline-3-carboxylic acid (3.1 g) as pale yellow needles, m.p. 261-265°C (decomposed with foaming) (which starts to color at around 235°C).
• 1-Hydroxypiperazine dihydrochloride (3.94 g) (which is prepared in Preparation 1), trimethylamine (21 ml) and dimethylsulfoxide (30 ml) are added to 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboyxlic acid (4.07 g), which is prepared according to the procecure described in Japanese Patent First Publication No. 30964/1981, and the mixture is heated at 100°C for 30 minutes. After cooling to room temperature, water (200 ml) is added to the mixture and the pH is adjusted to 7.0 with dil. HCI. The precipitated crystals are filtered, washed with water and dried.
• the product is recrystallized from a mixture of dimethylformamide and water to yield 1-ethyl-6,8-difluoro-1,4-dihydro-7-(4-hydroxypiperazin-1-yl)-4-oxoquinoline-3-carboxylic acid (4.3 g) as pale yellow needles, m.p. 253 -260°C (decomposed with foaming) (which starts to color brown at around 234°C).
• 1-Hydroxypiperazine dihydrochloride (1.03 g), triethylamine (35.6 g) and dimethylformamide (85 ml) are added to 6,7,8-trifiuoro-1-(2-fluoroethyl)-1,4,-dihydro-4-oxoquinoline-3-carboxylic acid (8.5 g), which is prepared by the procedure described in Japanese Patent First Publication No. 30964/1981, and the mixture is stirred for 1.5 hours at 100-105°C. After cooling to room temperature, the reaction mixture is poured into ice-water (500 ml) and the pH is adjusted to 7.0 with 50% aqueous acetic acid.
• 1-Hydroxypiperazine dihydrochloride (4.64 g), triethylamine (8.9 g) and dimethylsulfoxide (25 ml) are added to 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (5.0 g), which is prepared according to the procidures described in Japanese Patent First Publication No. 212474/1984, and the mixture is stirred with heating at 130°C for 45 minutes. After cooling the mixture to room temperature, the resulting crystals are filtered. To the crystals is added water (20 ml) and the mixture is stirred at 50°C for 1 hour.
• the insoluble substance is filtered and recrystallized from a mixture of dimethylformamide and water to afford 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(4-hydroxypiperazin-1-yl)-4-oxoquinoline-3-carboxylic acid (4.6 g) as pale yellow prisms, m.p. 223 -227°C (decomposed with foaming).
• the crude product is recrystallized from a mixture of dimethylformamide and water to afford 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(4-hydroxypiperazin-1-yl)-4-oxoquinoline-3-carboxylic acid (0.57 g) as pale yellow prisms.
• the melting point, infrared and nuclear magnetic resonance specta of this product are consistent with those of 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(4-hydroxypiperazin-1-yl)-4-oxoquinoline-3-carboxylic acid obtained in Example 5.
• the active ingredient, corn starch and microcrystalline cellulose are mixed with water throughly.
• the mixture is passed through a sieve to produce granules, which are dried.
• the granules are mixed with magnesium stearate and the mixture is compressed by a tablet machine to give tablets each weighing 250 mg.
• Granules containing 1-cyclopropyl-6,8,difluoro-1,4-dihydro-7-(4-hydroxypiperazin-1-yl)-4-oxoquinoline-3-carboxylic acid hydrochloride are prepared as follows:

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• 1986
  • 1986-09-30 US US06/913,382 patent/US4686221A/en not_active Expired - Fee Related
  • 1986-10-01 EP EP86113506A patent/EP0220523A3/de not_active Withdrawn

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